CTRI/2021/08/035759招募中3 期
A Randomised, Double-blind, Placebo-controlled, Phase III Study of Olaparib Maintenance Monotherapy in Participants with BRCA Wild Type Advanced (FIGO Stage III-IV) High Grade Serous or Endometrioid Ovarian Cancer Following Response to Standard First-line Platinum-based ChemotherapyMONO-OLA1
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 420
- 试验地点
- 8
- 主要终点
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of PFS in participants with Stage III or IV ovarian cancer (including fallopian tube and peritoneal cancers) with a BRCAwt HRD positive and BRCAwt type tumour and a CR or PR following standard first-line
研究概览
简要总结
This international study will be conducted atapproximately 100 study centers in 10 countries worldwide. Approximately 1200 participants with advanced Stage III to IV highgrade serous or endometroid ovarian, fallopian tube, or peritoneal cancer willbe screened in order to randomise approximately 420 participants with a BRCAwttumour who are in complete or partial response following standard first-lineplatinum-based chemotherapy treatment. Participants will be randomly assigned(2:1 ratio) to receive either Olaparib or placebo in one of the two groups :
· Group A:Olaparib tablets oral twice daily (n=280).
o Participantsin Group A will receive Olaparib tablets taken orally at a dose of twice daily for up to 2 years or untilobjective radiological disease progression as per RECIST 1.1 as assessed by theinvestigator, whichever is earlier, and as long as in the investigator’sopinion they are benefiting from treatment and do not meet any otherdiscontinuation criteria.
· Group B:Placebo tablets oral twice daily (n=140)
o Participantsin Group B will receive matching placebo tablets taken orally at a dose of twice daily for up to 2 years or untilobjective radiological disease progression as per RECIST 1.1 as assessed by theinvestigator, whichever is earlier, and as long as in the investigator’sopinion they are benefiting from treatment and do not meet any otherdiscontinuation criteria.
Randomisation will be stratified by:
· First-linetreatment outcome , HRD Status and Region
Treatment will be continued until diseaseprogression, unacceptable toxicity, or completion of 2 years of treatment.Participants with a complete response (no radiological evidence of disease) at2 years should stop treatment. Participants with evidence of disease at 2years, who in the opinion of the treating healthcare provider can derivefurther benefit from continuous treatment, can be treated beyond 2 years.
All participants who discontinue studyintervention will undergo an end-of-treatment visit (within 7 days ofdiscontinuation) and will be followed up for safety assessments 30 days (+ 7days) after their last dose of study intervention (ie, the safety follow-upvisit).
Following treatmentdiscontinuation, choice of subsequent therapy will be at the discretion of theInvestigator. Patients will be followed for second progression on a subsequenttreatment, defined according to local practice, and for survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified block randomization
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- Female
入选标准
- •Participants must be ≥18 years at the time of (pre-)screening. Type of Participant and Disease Characteristics
- •Histological and staging criteria: Female participants who must have histologically newly diagnosed high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) criteria
- •Participants are eligible if they fulfil any of the following surgical criteria: I.Stage III: primary debulking surgery with macroscopic residual disease post-surgery, II.neoadjuvant chemotherapy, or inoperable. III.Stage IV: primary debulking surgery regardless of residual disease, neoadjuvant IV.chemotherapy, or inoperable. Note: the receipt of intraperitoneal chemotherapy is permitted
- •Chemotherapy criteria: I.Participants must have received platinum-based chemotherapy consisting of a II.minimum of 6 treatment cycles and a maximum of 9, however, if platinum-based therapy must be discontinued early as a result of toxicities specifically related to the platinum regimen, participants must have received a minimum of 4 cycles of the platinum regimen. III.Participants must have, in the opinion of the investigator, clinical CR or PR as per RECIST 1.1 criteria with no measurable lesion > 2 cm on the post-treatment scan and have no clinical evidence of disease progression or a rising CA-125 level (see inclusion criterion 5), following completion of this chemotherapy course. IV.A participant who received interval debulking surgery must have had ≥ 2 postoperative cycles of platinum-based therapy.
- •Participants must meet one of the criteria specified below for pre-treatment CA-125 measurements as follows: I.CA-125 in the normal range or II.CA-125 decrease by ≥ 90% during their front-line therapy that is stable for at least 7 days (ie, no increase > 15% from nadir. If the first value is greater than the upper limit of normal (ULN), a second assessment must be performed at least 7 days after the first. If the second assessment is > 15% more than the first value, the participant is not eligible).
- •Participants should not have received bevacizumab with first-line chemotherapy or be planned to receive bevacizumab maintenance therapy.
- •Participants must be randomised within a maximum of 12 weeks from the last day of chemotherapy infusion (but no earlier than 3 weeks – see exclusion criterion 19).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation
- •Provision, at pre-screening, of a formalin-fixed, paraffin-embedded (FFPE) tumour sample to assess tBRCA status and for HRD testing centrally. The centrally performed tBRCA test results must be available prior to randomisation and must indicate that the participant has a BRCAwt tumour, defined by the absence of a deleterious or suspected deleterious BRCA mutation by central testing. Note: Tumour samples should be submitted for tBRCA and HRD testing only after a signed pre-screening informed consent form has been provided by the participant and if it appears the participant is likely to meet other eligibility criteria (see Section 8.6). To minimise bias, study participants, investigators and the site investigative staff will be blinded to HRD testing results and stratification/capping will be performed centrally by AstraZeneca.
- •Adequate organ and marrow function as follows: I.Haemoglobin ≥ 10.0 g/L with no blood transfusion in the past 28 days II.Absolute neutrophil count (ANC) ≥ 1.5 × 109/L III.Platelet count ≥ 100 × 109/L IV.Total bilirubin ≤ 1.5 × institutional ULN or ≤ 3 × institutional ULN in the presence of documented Gilbert s syndrome (unconjugated hyperbilirubinemia). V.Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase VI.[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase VII.[SGPT]) ≤ 2.5 × institutional ULN unless liver metastases are present in which case they may be ≤ 5.0 × institutional ULN. VIII.Participants must have estimated creatinine clearance (CrCL) of ≥ 51 mL/min using the Cockcroft-Gault equation (using actual body weight) or based on a 24 hour urine test or another validated test as per local practice: IX.CrCL (mL/min) equal Weight (kg) × (
- •Age) × 0.85 72 × serum creatinine (mg/dL) Sex
- •Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Reproduction
- •Negative serum pregnancy test within 28 days of Day 1 and confirmed negative urine pregnancy test prior to treatment on Day 1 for women of childbearing potential.
- •Participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly; see Appendix F). Women of childbearing potential must agree to use 1 highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to at least 1 month after the last dose. Non-sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. Informed Consent
- •Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. All participants must sign both the pre-screening ICF and the main ICF. The pre-screening ICF will be provided for consent of mandatory tBRCA/HRD testing.
排除标准
- •Medical Conditions
- •Participants with stable disease or progressive disease on the post-treatment scan or clinical evidence of progression at the end of the participant s first-line chemotherapy treatment, or any evidence of progressive disease prior to randomisation.
- •Participant has mucinous or clear cell subtypes of epithelial ovarian cancer, carcinosarcoma, undifferentiated ovarian cancer, non-epithelial ovarian cancer, borderline tumours or low grade epithelial ovarian tumours (applies to fallopian tube and primary peritoneal tumours where applicable).
- •3 Participants with Stage III disease who have had complete cytoreduction (ie, no macroscopic residual disease) at their primary debulking surgery.
- •4 Participants who have undergone ˃ 2 debulking (cytoreductive) surgeries.
- •History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention including adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, Grade 1 endometrial carcinoma Participants with a history of localised triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the participant remains free of recurrent or metastatic disease.
- •As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases or active, uncontrolled infection, including but not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, recent [within 3 months] myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography [HRCT] scan) which, in the investigator s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
- •Participants unable to swallow orally administered medication and participants with gastrointestinal disorders that would preclude adequate absorption, distribution, metabolism, or excretion of olaparib.
- •Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.
- •Current signs or symptoms of bowel obstruction, including sub-occlusive disease related to the underlying disease.
- •Myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or features suggestive of MDS/AML.
- •Spinal cord compression or brain metastases (including leptomeningeal disease) unless asymptomatic, stable, and not requiring steroids ≥ 4 weeks prior to start of study intervention.
- •A scan to confirm the absence of brain metastases is not required.
- •Participants with known active hepatitis (ie, hepatitis B or C).
- •I.Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result.
- •Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
- •II.Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- •Known to have tested positive for human immunodeficiency virus (HIV) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- •History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
- •Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study physician.
- •Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
- •16 Participant is planning to donate blood during the study or for 90 days after the last dose of study treatment.
- •Participant is immunocompromised (participants with splenectomy are allowed).
- •Prior/Concomitant Therapy
- •Prior exposure to a PARP inhibitor, including olaparib.
- •Concomitant use of known strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) within 2 weeks prior to first dose of study intervention (see Appendix H 1).
- •Concomitant use of known strong CYP3A inducers (eg.
- •phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, St John s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, modafinil) (see Appendix H 1).
- •The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other strong/moderate CYP3A inducers.
- •Any concurrent anticancer treatment.
- •Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
- •Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention.
- •Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
- •Prior/Concurrent Clinical Study Experience
- •Previous randomisation in the present study.
- •Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 12 months prior to randomisation or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
- •Participants with known hypersensitivity to olaparib or any of its excipients.
- •Other Exclusions
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- •Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
结局指标
主要结局
To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of PFS in participants with Stage III or IV ovarian cancer (including fallopian tube and peritoneal cancers) with a BRCAwt HRD positive and BRCAwt type tumour and a CR or PR following standard first-line
时间窗: PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the | investigator at the local site, or death due to any cause. | Tumour assessment (CT/MRI) will be performed at baseline (screening) and every 12 weeks (± 7 days) relative to the date of randomisation until RECIST 1.1-defined radiological PD.
platinum-based chemotherapy treatment.
时间窗: PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the | investigator at the local site, or death due to any cause. | Tumour assessment (CT/MRI) will be performed at baseline (screening) and every 12 weeks (± 7 days) relative to the date of randomisation until RECIST 1.1-defined radiological PD.
次要结局
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of OS in participants with Stage III or IV ovarian cancer (including fallopian tube and peritoneal cancers) with a BRCAwt HRD positive tumour and a CR or PR following standard first line platinum based chemotherapy treatment(OS is defined as time from randomisation until the date of death due to any cause. The comparison will include all randomised participants as randomised, regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy.)
- To assess disease-related symptoms, functioning, and HRQoL in participants treated with olaparib compared with placebo using the EORTC QLQ C30 questionnaire and its ovarian specific module, EORTC QLQ OV28 in participants with BRCAwt tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(Change from baseline in EORTC QLQ C30 and EORTC QLQ OV28 selected scores.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of TFST in participants with a BRCAwt HRD positive tumour and a CR or PR following standard first-line platinum-based chemotherapy treatment(TFST is defined as time from randomisation until the start date of the first subsequent anti-cancer therapy after discontinuation of randomised treatment, or death due to any cause.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of TFST in participants with a BRCAwt tumour and a CR or PR following standard first line platinum based chemotherapy treatment(TFST is as defined in the row above.)
- Safety - To assess the safety and tolerability of olaparib as compared with placebo in participants with standard(Safety and tolerability will be evaluated in terms of AEs/SAEs, physical examination, vital signs (including blood pressure and pulse), and clinical laboratory)
- To demonstrate superiority of by assessment of second progression free survival  in participants with standard(Time from randomisation to second progression or death (PFS2) is as defined in the row above.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of OS in participants with Stage III or IV ovarian cancer (including fallopian tube and peritoneal cancers) with a BRCAwt tumour and a CR or PR following standard first-line platinum-based chemotherapy treatment.(OS is as defined in the row above.)
- To demonstrate superiority of by assessment of second progression free survival (PFS2) in participants with standard(Time from randomisation to second progression or death (PFS2) is defined as the time from the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death. The date of second progression will be recorded by the Investigator in the eCRF and defined according to local standard clinical practice.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of TSST in participants with a BRCAwt(TSST is as defined in the row above.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of time to study intervention discontinuation or death (TDT) in participants with a BRCAwt HRD positive tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(TDT is defined as time from randomisation until discontinuation of treatment for any reason, including disease progression, toxicity and death.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of time to study intervention discontinuation or death (TDT) in participants with a BRCAwt tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(TDT is as defined in the row above.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of time to earliest progression by RECIST 1.1 or CA 125 or death in participants with a BRCAwt tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(Time to earliest progression by RECIST 1.1 or CA 125 or death as defined in the row above. The comparison will include all randomised participants as randomised.)
- To assess disease-related symptoms, functioning, and HRQoL in participants treated with olaparib compared with placebo using the EORTC QLQ C30 questionnaire and its ovarian specific module, EORTC QLQ OV28 in participants with a BRCAwt HRD positive tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(Change from baseline in EORTC QLQ C30 and EORTC QLQ OV28 selected scores.)
- To demonstrate superiority of olaparib as maintenance treatment relative to placebo by assessment of time to earliest progression by RECIST 1.1 or CA 125 or death in participants with a BRCAwt ¬¬HRD positive tumour and a CR or PR following standard first-line platinum based chemotherapy treatment(Time to earliest progression by RECIST 1.1 or CA 125 or death will be measured from time of randomisation to the earlier date of RECIST 1.1 or CA-125 progression or death by any cause. The comparison will include all randomised participants as randomised.)
研究者
研究点 (8)
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